Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and/or threonine residues of proteins. Protein kinases, for example, receptor tyrosine kinases (RTKs), may act as growth factor receptors and play a central role in signal transduction pathways regulating cellular functions, such as cell cycle, cell growth, cell differentiation, and cell death. Aberrant or excessive activity or disregulation of the activity of RTKs has been observed in many disease states, including benign and malignant proliferative disorders, as well as inflammatory disorders and immune system disorders that result from inappropriate activation of the immune system to cause, for example, autoimmune diseases.
Inhibitors of certain kinases may also have utility in the treatment of diseases where the kinase, although not misregulated, is essential for the maintenance of the disease state. In these cases, inhibition of the kinase activity would act either as a palliative or as a cure for these diseases. For example, many viruses, such as human papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle. See, e.g., Vousden, FASEB J. 7, 872-879 (1993). Inhibition of essential S-phase initiating activities by kinase inhibitors prevents cells from entering the DNA synthesis phase after viral infection, thereby disrupting the virus life cycle and preventing virus replication. The same principle may also be used to protect normal cells of the body from the toxicity of cell-cycle-specific chemotherapeutic agents. See, e.g., Stone et al., Cancer Res. 56, 3199-3202 (1996); Kohn et al., J. Cell. Biochem. 54, 44-52 (1994).
Fms-like tyrosine kinase 3 (FLT3), which is also known as FLK-2 (fetal liver kinase 2) and STK-1 (stem cell kinase 1), plays an important role in the proliferation and differentiation of hematopoietic stem cells. FLT3 receptor kinase is expressed in normal hematopoietic cells, placenta, gonads, and brain. This kinase is expressed at very high levels on the cells of more than 80% of myeloid patients and a fraction of acute lymphoblastic leukemia patients. This enzyme can also be found on the cells from patients with chronic myeloid leukemia in lymphoid blast crisis.
In addition, FLT3 kinase is mutated in 30% of acute myeloid leukemia (AML) and in a subset of acute lymphoblastic leukemia (ALL). See, e.g., Gilliland et al., Blood 100, 1532-1542 (2002); Stirewalt et al., Nat. Rev. Cancer 3, 650-665 (2003). The most common activating mutations in FLT3 are internal tandem duplications within the juxtamembrane region. Point mutations, insertions, or deletions in the kinase domain are less common. Some of these mutant FLT3 kinases are constitutively active. FLT3 mutations have been associated with a poor prognosis. See, e.g., Malempati et al., Blood 104, 11 (2004).
More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML. See, e.g., Levis et al. Int. J. Hematol. 82, 100-107 (2005). It has been reported that some small-molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and prolonging survival of mice that express mutant FLT3 in their bone marrow cells. See, e.g., Levis et al., Blood 99, 3885-3891 (2002); Kelly et al., Cancer Cell 1, 421-432 (2002); Weisberg et al., Cancer Cell 1, 433-443 (2002); Yee et al., Blood 100, 2941-2949 (2002).
In addition, cancer is a major public health problem worldwide. In the United States alone, approximately 560,000 people died of cancer in 2006. See, e.g., U.S. Mortality Data 2006, National Center for Health Statistics, Centers for Disease Control and Prevention (2009). Many types of cancer have been described in the medical literature. Examples include, but are not limited to, cancer of the blood, bone, skin, lung, colon, breast, prostate, ovary, brain, kidney, bladder, pancreas, and liver. The incidence of cancer continues to climb as the general population ages and as new forms of cancer develop. A continuing need exists for effective therapies to treat subjects with cancer.
Kinase inhibitors are currently being explored for the treatment of diseases such as proliferative diseases, FLT-3 mediated diseases, and cancers. Despite the success in identification of small molecules that inhibit kinases, there continues to be a need for new kinase inhibitor compounds and safe, efficient, scalable, and/or economically viable processes to prepare these kinase inhibitor compounds, such as, for example, processes to prepare kinase inhibitors on a commercial scale suitable for human use, and/or processes having other potential advantages.
Provided herein are new processes to prepare N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea. N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea is disclosed in U.S. Patent Application Publication Nos. 2007/0232604, 2009/0123418, and 2009/0131426, each of which is incorporated herein by reference in their entireties.
Citation of any references in this Section of the application is not to be construed as an admission that such references is prior art to the present application.